MedDRA®

DATA RETRIEVAL AND PRESENTATION:

POINTS TO CONSIDER

ICH-Endorsed Guide for MedDRA Users on Data Output

Release 3.5 Based on MedDRA Version 16.0

1 April 2013

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Table of Contents Section 1 – INTRODUCTION............................................................................... 1

1.1 – Objectives of this Document ..................................................................... 2

1.2 – Reasons to Use MedDRA ........................................................................ 2 1.3 – How to Use this Document ....................................................................... 2

Section 2 – GENERAL PRINCIPLES .................................................................. 3 2.1 – Quality of Source Data ............................................................................. 3

2.1.1 Data conversion considerations ........................................................ 3

2.1.2 Impact of data conversion method .................................................... 4 2.2 – Documentation of Data Retrieval and Presentation Practices .................. 4 2.3 – Do Not Alter MedDRA .............................................................................. 5 2.4 – Organization-Specific Data Characteristics .............................................. 5

2.5 – Characteristics of MedDRA that Impact Data Retrieval and Analysis ....... 6 2.5.1 Grouping terms (HLTs and HLGTs) .................................................. 6

2.5.1.1 Review terms within a grouping term ............................................ 6

2.5.2 Granularity ......................................................................................... 7 2.5.3 Multi-axiality ...................................................................................... 7

2.5.3.1 Primary SOC assignment rules ..................................................... 7 2.5.3.2 Non multi-axial SOCs .................................................................... 8 2.5.3.3 Clinically related PTs ................................................................... 10

2.6 – MedDRA Versioning ............................................................................... 10

Section 3 – GENERAL QUERIES AND RETRIEVAL ....................................... 13 3.1 – General Principles .................................................................................. 13

3.1.1 Graphical displays ........................................................................... 15

3.1.2 Patient subpopulations .................................................................... 15

3.2 – Overall Presentation of Safety Profiles ................................................... 15 3.2.1 Overview by primary System Organ Class ...................................... 16

3.2.2 Overall presentations of small datasets ........................................... 17 3.2.3 Focused searches ........................................................................... 18

3.2.3.1 Focused searches by secondary SOC assignments ................... 18

Section 4 – STANDARDISED MedDRA QUERIES ........................................... 19

4.1 – Introduction ............................................................................................. 19 4.2 – SMQ Benefits ......................................................................................... 20 4.3 – SMQ Limitations ..................................................................................... 20 4.4 – SMQ Modifications and Organization-Constructed Queries ................... 20

4.5 – SMQs and MedDRA Version Changes .................................................. 20 4.6 – SMQs – Impact of MedDRA Legacy Data Conversion ........................... 21 4.7 – SMQ Change Requests ......................................................................... 22 4.8 – SMQ Technical Tools ............................................................................. 22 4.9 – SMQ Applications ................................................................................... 22

4.9.1 Clinical trials .................................................................................... 23 4.9.2 Postmarketing .................................................................................... 23

4.9.2.1 Focused searches ....................................................................... 23 4.9.2.2 Signal detection ........................................................................... 23

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4.9.2.3 Single case alert .......................................................................... 23 4.9.2.4 Periodic reporting ........................................................................ 24

4.10 – SMQ Search Options ........................................................................... 24 4.10.1 Narrow and broad searches ......................................................... 24 4.10.2 Hierarchical SMQs ....................................................................... 25 4.10.3 Algorithmic SMQs ........................................................................ 25

4.11 – SMQ and MedDRA Grouping Terms .................................................... 26 Section 5 – CUSTOMIZED SEARCHES ........................................................... 27

5.1 – Modified MedDRA Query Based on an SMQ ......................................... 27 5.2 – Customized Queries ............................................................................... 28

Section 6 – APPENDIX ...................................................................................... 29

6.1 – Links and References ............................................................................. 29

6.2 – Membership of the ICH Points to Consider Working Group ................... 30

6.2.1 Current members of the ICH Points to Consider Working Group ........ 31 6.2.2 Former members of the ICH Points to Consider Working Group .... 31

6.3 – Figures ................................................................................................... 32

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Section 1 – INTRODUCTION The Medical Dictionary for Regulatory Activities terminology (MedDRA) was designed for sharing regulatory information for human medical products. However, unless users achieve consistency in how they assign terms to verbatim reports of symptoms, signs, diseases, etc., and in methods for data retrieval and evaluation, use of MedDRA cannot have the desired harmonizing effect in the exchange of coded data. MedDRA is a large terminology with very specific (“granular”) terms called Lowest Level Terms (LLTs) that serve to accurately record the reporter’s words (verbatim term). LLTs are generally synonyms linked to their parent terms known as Preferred Terms (PTs). PTs are also relatively specific and large in number. While a highly granular terminology such as MedDRA reduces the need for interpretation at data entry, it impacts the processes of data retrieval, sorting and presentation necessary for support of drug development, pharmacovigilance and risk management. The hierarchical structure of MedDRA facilitates data retrieval by providing grouping terms (High Level Terms [HLTs] and High Level Group Terms [HLGTs]) that aggregate the very specific terms used for coding into broader medical categories. MedDRA’s multi-axiality (assignment of a PT to more than one System Organ Class [SOC]) allows flexibility in data retrieval via primary and secondary paths. While grouping terms and multi-axiality permit a reasonable first approach to data retrieval, the complexity of MedDRA requires guidance to optimize the results. This Data Retrieval and Presentation: Points to Consider (DRP: PTC) document is an ICH-endorsed guide for MedDRA users. It is updated in step with new MedDRA versions and is a companion document to MedDRA. It was developed and is maintained by a working group charged by the ICH Steering Committee. The working group consists of regulatory and industry representatives of the European Union, Japan and the United States, as well as representatives from the Canadian regulatory authority, the MedDRA Maintenance and Support Services Organization (MSSO) and the Japanese Maintenance Organization (JMO). (See Appendix, Section 6.2 for list of members). The principles described in this document are most effective when used in conjunction with the principles described in the MedDRA Term Selection: Points to Consider document for data entry (coding). This document provides data retrieval and presentation options for either industry or regulatory purposes. Although MedDRA includes some data retrieval tools, this document addresses data retrieval in a broader context.

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Examples in this document are based on MedDRA Version 16.0; they are intended to facilitate reader understanding and are not intended to imply regulatory requirements. Figures referenced in the text are found in the Appendix, Section 6.3. 1.1 – Objectives of this Document The objective of the DRP: PTC document is to demonstrate how data retrieval options impact the accuracy and consistency of data output. For example, certain drugs or therapeutic areas may need a customized approach for data output. Options for data input described in the MedDRA Term Selection: Points to Consider document – or in organization-specific coding guidelines – should also be taken into consideration. Organizations are encouraged to document their data retrieval and output strategies, methods and quality assurance procedures in organization-specific guidelines which should be consistent with this DRP: PTC document. 1.2 – Reasons to Use MedDRA MedDRA is used to report adverse reaction/adverse event (AR/AE) terms in individual case reports – both on paper or electronically. Its structure allows for aggregation of those reported terms in medically meaningful groupings to facilitate analysis of safety data. MedDRA can also be used to list AR/AE data in reports (tables, line listings, etc), compute frequencies of similar AR/AEs, and capture and analyze related data such as product indications, investigations, and medical and social history. 1.3 – How to Use this Document The principles described in this document apply to all data encoded with MedDRA with a focus on aggregated data. This document does not address the use of MedDRA for single case reporting, labeling, medical evaluation and statistical methodology. This Points to Consider document aims to help all MedDRA users, since the MedDRA terminology itself contains no specific guidelines for its use. The document provides a framework to foster consistent use of MedDRA for data analysis and presentation for medically meaningful review and analysis of clinical data. This document describes the features of MedDRA and highlights the impact of MedDRA’s structure, rules and conventions on data output. Examples and options described in the document are not intended to communicate specific regulatory reporting requirements or address specific database issues. This document cannot address every situation, therefore, medical judgment should always be applied.

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The document is not a substitute for MedDRA training. It is essential for users to have knowledge of MedDRA’s structure and content. For optimal use of MedDRA, one should refer to the MedDRA Introductory Guide, the Introductory Guide for Standardised MedDRA Queries (SMQs) (See Appendix, Section 6.1) and the MedDRA Term Selection: Points to Consider document; these documents are available with each MedDRA subscription. Section 2 – GENERAL PRINCIPLES 2.1 – Quality of Source Data High quality data output occurs when the quality of the information originally reported is maintained with consistent and appropriate term selection. Organizations should pursue continuous oversight of data quality. Data quality issues are also addressed in the MedDRA Term Selection: Points to Consider document.

2.1.1 Data conversion considerations Give special consideration to the method used to convert data from other terminologies into MedDRA. The methods used can impact retrieval and presentation strategies.

Method 1 – Data converted from legacy terminology terms to MedDRA

Results will reflect the specificity of the previous terminology

The benefits of the greater specificity of MedDRA are not attained

Example

Reported Legacy Term MedDRA Term

Bowel ischaemia Gastrointestinal Disorder Gastrointestinal

disorder

Method 2 – Data converted from the original reported terms (verbatim terms) to MedDRA terms

Example

Reported Legacy Term MedDRA Term

Bowel ischaemia Gastrointestinal Disorder Bowel ischaemia

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Document the data conversion method used, including the date of the conversion.

2.1.2 Impact of data conversion method Combining the two conversion methods described above can affect interpretation of data output.

Example

Data Output with Combined Data Conversion Methods

If data have been converted directly from legacy terminology terms to

MedDRA terms (Method 1), and if newly acquired data are coded directly

from reported terms to MedDRA, the resulting differences in specificity

could make interpretation difficult. When designing a search strategy, it may be useful to examine the reported terms for data converted using Method 1. If the search has been based on specific MedDRA terms, data previously coded to non-specific terms may be otherwise overlooked.

Example

Impact of Method 1 Conversion on Search Strategy

If searching with MedDRA PT Bowel ischaemia, cases of bowel ischemia

coded with the legacy term Gastrointestinal disorder would be missed. In

this case, it would be important to know the date

of the legacy data conversion. To conduct a search requiring this level of detail, it might be necessary to review or recode from the reported terms. For legacy data, this information might be found in fields other than those for ARs/AEs. 2.2 – Documentation of Data Retrieval and Presentation Practices It is important to document MedDRA term selection conventions, data retrieval and output strategies (including SMQs and other queries) and quality assurance procedures. Organization-specific strategies should be consistent with the Points to Consider documents and should include:

MedDRA version used for the search

Search strategy methods (sufficiently detailed to be reproducible)

Version update processes

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Processes for creating and maintaining customized MedDRA queries

2.3 – Do Not Alter MedDRA MedDRA is a standardized terminology with a pre-defined term hierarchy that should not be altered. Users must not make ad hoc structural alterations to MedDRA, including changing the primary SOC allocation; doing so would compromise the integrity of this standard. If terms are found to be incorrectly placed in the MedDRA hierarchy, a change request should be submitted to the MSSO. 2.4 – Organization-Specific Data Characteristics Although MedDRA is a standardized terminology, different organizations have implemented it is various ways. It is important to understand organization-specific data characteristics and implementation strategies. Each organization should have access to a MedDRA specialist to provide expert advice and who has the knowledge of the following database characteristics:

Database structure (how the MedDRA hierarchy is stored and used)

Data storage (e.g., level of term, synonym/reported term)

Data conversion from other terminologies (if applicable)

Coding practices over time

Example

Impact of Coding Practices Over Time

Consider the impact of gender-specific terms when comparing MedDRA

coded data to data coded with an older terminology that may not have had

corresponding gender-specific terms. If the prior terminology had only a

single, gender-neutral term for “breast cancer”, consider the impact of

selecting gender-specific breast cancer terms in MedDRA for current data.

Limitations or restrictions

Example

Output or Display of Multi-axial PTs

Do not assume that PTs in their secondary SOC locations will be seen when

searching in a specific HLT or HLGT since the database configuration may

not allow output or display by the secondary path.

Term selection principles used

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o Selecting more than one term when coding a medical condition increases counts of terms.

o Selecting a diagnosis term only (and not terms for signs and symptoms) reduces the counts of terms.

o The adverse event profile resulting when both diagnosis and signs/symptoms terms are coded may appear different than when the diagnosis only is coded. Always consider the organization’s coding conventions when using or comparing data from other databases (e.g., co-developing or co-marketing partners, regulatory authorities).

2.5 – Characteristics of MedDRA that Impact Data Retrieval and Analysis MedDRA’s structure, rules and conventions are detailed in the MedDRA Introductory Guide.

Keep the following MedDRA characteristics in mind for data retrieval and presentation:

2.5.1 Grouping terms (HLTs and HLGTs) The HLT and HLGT levels are an additional tool for data analysis and retrieval as they provide clinically relevant groupings of terms.

Example

Cardiac Arrhythmias

HLGT Cardiac arrhythmias

HLT Cardiac conduction disorders

HLT Rate and rhythm disorders NEC

HLT Supraventricular arrhythmias

HLT Ventricular arrhythmias and cardiac arrest

2.5.1.1 Review terms within a grouping term Review terms within the HLGT or HLT of interest to be sure that all terms therein are suited for the purpose of the output.

Example

Blood Pressure Terms

HLT Vascular tests NEC (incl blood pressure)

PT Blood pressure

PT Blood pressure abnormal

PT Blood pressure decreased

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Blood Pressure Terms

PT Blood pressure increased

Note that terms for increased and decreased blood pressure are grouped

under a single HLT which also includes PTs for pulmonary arterial pressure,

vascular resistance, hemodynamic tests, etc.

2.5.2 Granularity MedDRA PTs are more specific (“granular”) than comparable terms in other terminologies. Figure 1 illustrates how data coded to a single concept from another terminology may be coded to several PTs in MedDRA. Related events that may have been represented by a single term in another terminology may be represented by more than one MedDRA PTs. The potential impact of this on signal detection should be kept in mind.

2.5.3 Multi-axiality Multi-axiality means that a PT may exist in more than one SOC. This allows terms to be grouped in different, but medically appropriate, ways (e.g., by etiology or organ system). Each PT is assigned one primary SOC; all other SOC assignments for that PT are called “secondary”. Having a single primary SOC prevents double counting of events when outputting data from all SOCs. All possible secondary SOC assignments for any given PT may not be present in MedDRA. However, new or revised SOC assignments can be created as a result of the change request process.

2.5.3.1 Primary SOC assignment rules Primary SOC assignment rules are described in the MedDRA Introductory Guide. These rules affect the way terms are placed in MedDRA and determine their data display by SOC. Because these rules allow for terms related to a particular medical condition to be in more than one SOC, users should be familiar with the general structure and content of all MedDRA SOCs to be sure that data are not overlooked.

Example

Type of Disorder Primary SOC Rule Example Comment

Congenital All terms for

congenital

disorders have as

their primary SOC

assignment SOC

Congenital, familial

PT Congenital absence of bile

ducts has a primary

SOC assignment of

SOC Congenital, familial and genetic

The secondary SOC

assignment for these

terms is their “site of

manifestation” SOC

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Type of Disorder Primary SOC Rule Example Comment

and genetic disorders

disorders and a

secondary SOC

assignment of SOC

Hepatobiliary disorders

Neoplastic All terms for

malignant and

benign neoplasms

(except cysts and

polyps) have as

their primary SOC

assignment SOC

Neoplasms benign, malignant and

unspecified (incl cysts and polyps)

PT Skin cancer has

a primary SOC

assignment of SOC

Neoplasms benign, malignant and

unspecified (incl cysts and polyps) and a secondary

SOC assignment of

SOC Skin and subcutaneous

tissue disorders

Cyst and polyp terms

are an exception to

this rule. The primary

SOC assignment for

cyst and polyp terms is

the “site of

manifestation” SOC,

and the secondary SOC

is SOC Neoplasms benign, malignant and unspecified (incl cysts

and polyps) Infectious All terms for

infectious

disorders have as

their primary SOC

assignment SOC

Infections and infestations

PT Enterocolitis infectious has a

primary SOC

assignment of SOC

Infections and infestations and a

secondary SOC

assignment of SOC

Gastrointestinal disorders

The secondary SOC

assignment for these

terms is their “site of

manifestation” SOC

If a PT links to more than one of these three SOCs, the following priority is used to determine the primary SOC:

SOC Congenital, familial and genetic disorders

SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps)

SOC Infections and infestations

2.5.3.2 Non multi-axial SOCs Terms in the following three SOCs do not have multi-axial links:

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SOC Investigations SOC Surgical and medical procedures SOC Social circumstances This is important when designing queries and other retrieval strategies because one cannot rely on multi-axiality to locate all terms of interest in MedDRA.

Example

Impact of Non Multi-Axial SOCs on Data Queries

When querying a database for events or cases of thrombocytopenia, data

coded to PTs in SOC Blood and lymphatic system disorders is a logical

starting point. Additionally, data coded to terms in SOC Investigations –

such as PT Platelet count decreased – and data coded to terms in SOC

Surgical and medical procedures - such as PT Platelet transfusion – could

also be of interest. Neither of these PTs has a link to SOC Blood and lymphatic system disorders.

Failure to consider data coded in the non multi-axial SOCs could lead to

incomplete analysis of thrombocytopenia. As noted above, terms for test results are in SOC Investigations and do not have multi-axial links to terms for corresponding medical conditions. Keep this in mind when reviewing tables and data listings of MedDRA coded data.

Example

Terms for Test Results in SOC Investigations

When querying a database for events or cases of hepatic abnormalities, data

coded to PTs in SOC Hepatobiliary disorders is a logical starting point.

Additionally, data coded to terms in SOC Investigations – such as PT Liver function test abnormal – and data coded to terms in SOC Surgical and

medical procedures - such as PT Liver transplant – could also be of interest.

Neither of these PTs has a link to SOC Hepatobiliary disorders.

Failure to consider data coded in the non multi-axial SOCs could lead to

incomplete analysis of hepatic abnormalities.

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Figure 2 further illustrates the impact of data coded as test results vs. the corresponding medical condition.

2.5.3.3 Clinically related PTs Clinically related PTs might be overlooked or not recognized as belonging together because they might be in different groupings within a single SOC or they may be located in more than one SOC. (See Section 2.5.3).

Example

Similar Skin Conditions in Different Groupings

HLGT Epidermal and dermal conditions

HLT Bullous conditions

PT Stevens-Johnson syndrome

PT Toxic epidermal necrolysis

HLT Exfoliative conditions

PT Dermatitis exfoliative

PT Dermatitis exfoliative generalised

PT Nikolsky's sign

PT Skin exfoliation The frequency of a medical concept may be underestimated if the above points are not considered; this may impact interpretation of data. (See Section 3.2). MedDRA SOCs group terms by body systems, etiologies and specialized purposes. Data may be coded to terms in SOCs that had not been anticipated by the user. Keep in mind the potential impact of multi-axiality on frequencies of the medical condition of interest.

Example

Preferred Term Primary SOC

Post procedural haemorrhage Injury, poisoning

and procedural complications

Chest pain General disorders and administration

site conditions

2.6 – MedDRA Versioning MedDRA is updated twice yearly. Version “X.0” contains both simple and complex changes; version “X.1” contains only simple changes.

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Organizations should be aware of the types of MedDRA changes for their possible impact on data output.

Types of MedDRA Changes

Simple Changes Complex Changes

Add a PT (new medical concept)

Move an existing PT from one HLT to

another

Demote a PT to LLT level

Add or remove a link to an existing

PT

Add an LLT

Move an existing LLT from one PT to

another

Promote an LLT to PT level

Make a current LLT non-current or a

non-current LLT current

Changing the primary SOC allocation

Changes to SMQs

Add or change multi-axial links

Add new grouping terms

Merge existing grouping terms

Restructure a SOC

Both simple and complex changes impact retrieval and presentation strategies. Users should read the documentation provided with each MedDRA release, especially the What’s New document. The MSSO and JMO provide tools to assist the user in comparing the changes between MedDRA versions. The Version Report (provided by the MSSO and JMO) is a spreadsheet listing all changes between the current version of MedDRA and the one previous to it; this spreadsheet is provided with each new release of MedDRA. The MSSO also provides the MedDRA Version Analysis Tool (MVAT) that facilitates identification and understanding of the impact of changes between any two MedDRA versions, including non-consecutive ones. (See Appendix, Section 6.1 of this document; also, see Section 4.1.1 of the MedDRA Term Selection: Points to Consider document). Organizations should plan and document their strategy for handling MedDRA version updates. When planning or performing data retrieval and presentation, the MedDRA version used should be documented. Keep in mind that MedDRA changes may impact previous data retrieval approaches and results, including event frequencies.

Example

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Impact of Version Changes – Demoted PT

PT AIDS encephalopathy was included in a query developed using terms in

MedDRA Version 15.1. If the query had been re-run on data using MedDRA

Version 16.0, these events would not have been found at the PT level

because PT AIDS encephalopathy had been demoted to an LLT and linked to

PT AIDS dementia complex. See Figure 3.

Example

Impact of Version Changes – Change of Primary SOC Assignment

PT Anaesthetic complication foetal had a primary link to SOC Pregnancy, puerperium and perinatal conditions and a secondary link to SOC Injury,

poisoning and procedural complications in MedDRA Version 15.1. In Version

16.0, the primary SOC assignment was changed to SOC Injury, poisoning and procedural complications and the secondary assignment to SOC Pregnancy, puerperium and perinatal conditions. In a primary SOC output of data, PT

Anaesthetic complication foetal will seem to have “disappeared” from

SOCPregnancy, puerperium and perinatal conditions. Terms used to construct queries should be in the same MedDRA version as the data being queried. An organization’s legacy data may be coded in more than one version of MedDRA. New terms may have been included in a new query built in MedDRA Version 16.0; depending upon the organization’s versioning method, these new terms might not be present in the older data. This could lead to search results that are incomplete. A search built with terms of an earlier MedDRA version (e.g., used previously on a now closed study) might not identify all relevant data in an integrated safety summary (ISS) containing data coded in a later version of MedDRA. Queries stored in an organization’s system should be updated to the appropriate version of MedDRA before using them on new data. Advice on how an organization should handle new MedDRA versions is not within the scope of this document. (See MedDRA Term Selection: Points to Consider, Appendix 4.1). Some databases may contain data of multiple studies coded in different versions of MedDRA. This may impact aggregation of those data (e.g., in an ISS). Refer to MSSO documents on versioning options for clinical trial and postmarketing data for more information (http://meddramsso.com/subscriber_library.asp).

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Section 3 – GENERAL QUERIES AND RETRIEVAL 3.1 – General Principles Data retrieval is performed for summary and analysis of clinical trial data, pharmacovigilance, medical information questions and for a number of other purposes. The search strategies, methods and tools used to retrieve data might differ based on the intended use of the output. A general approach for data retrieval is outlined in the chart below.

Define medical issues/safety question

(See Section 3.1)

Develop MedDRA search strategy

(See Section 3.2.3)

SMQSOC with

2ry Links

Customized

search

Grouping

terms

(HLGT, HLT)

Customized

Query

Modified

MedDRA Query

based on an

SMQ

Retrieval of events or cases matching search strategy

Assessment of data (events or cases) related to medical/safety

issue or question

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Prior to data retrieval, there may be known or potential safety issues that need detailed investigation. Information from pre-clinical studies, clinical trials post-marketing surveillance, class effects of similar products, and regulatory queries may identify areas of possible focus; these may affect the strategy for aggregating search terms, the methodology, and the way data are displayed. Be aware of database characteristics, organization-specific data entry conventions, data sources, the size of the database, and the version of MedDRA used for coding all data. Archived searches may be available to the user, especially those used in pharmacovigilance; these may be suitable for use if updated. When presenting adverse event data, it is important to display and to group related events (i.e., events that represent the same condition of interest) so that the true occurrence rate of an event is not obscured. Search strategies should be documented. The search output alone may not suffice for data assessment (e.g., frequency of a condition). Search results should be evaluated against the question originally posed. Sorting related events into categories can be challenging. A search that is too narrowly focused might exclude events of potential relevance; a search that is too broad might make it difficult to identify a trend or signal. Careful interpretation is required when grouping terms that correspond to a potential event or medical condition for analysis (whether a syndrome or not). The purpose is to identify trends that may require further analysis, including review of individual cases. For complex queries, create a data analysis plan including a definition of the medical condition of interest. An interdisciplinary discussion might be helpful to identify the most suitable methods and tools relevant to the query. These principles may apply to the types of searches listed in the table below:

Example

Types of Searches – Application of General Principles

Safety profile overview in a summary report, Periodic Safety Update Report

(PSUR), ISS, etc.

Comparing frequencies of ARs/AEs reporting rates for spontaneous reports

or incidence for studies)

Analysis of a specific safety concern

Identifying patient subpopulations at risk (search of medical history)

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3.1.1 Graphical displays Graphical displays can be useful especially with large datasets. Such displays allow quick visual representation of potential signals. Organizations are encouraged to use graphs for data display. Histograms, bar charts, and pie charts can be useful as can more complex, statistically-derived displays (e.g., data mining algorithms). Examples of these types of displays are in the Appendix, Section 6.3.

3.1.2 Patient subpopulations Pediatric and gender-specific adverse event terms lists – available on the MSSO and JMO Web sites – may aid in data retrieval for these subpopulations (See Appendix, Section 6.1). However, it is necessary to refer to individual database fields for demographics. 3.2 – Overall Presentation of Safety Profiles The aims of an overall safety profile presentation are to:

Highlight distribution of ARs/AEs

Identify areas for in depth analysis

Present the data in a way that allows for easy recognition of patterns of terms potentially related to the relevant medical conditions. There are various ways to do this ranging from a full listing of terms to sophisticated statistical approaches such as data mining techniques (for reference, see ICH E2E: Pharmacovigilance Planning Document; link listed in the Appendix, Section 6.1). Historically, the standard approach has been to display data by Body System (or System Organ Class) and Preferred Term corresponding to SOCs and PTs in MedDRA. Due to MedDRA’s unique characteristics (multi-axiality, granularity), this PT-SOC approach may need to be augmented with other types of data outputs (e.g., secondary SOC output, display by grouping terms [HLTs, HLGTs], etc.), depending on the reason for the output. For example, if a number of reports describe a similar medical condition, they could be represented by:

Many different PTs (dilution of signal)

Different grouping terms

Different SOCs

SOCs where the user would not intuitively expect them (e.g., SOC General disorders and administration site conditions, SOC Pregnancy, puerperium and perinatal conditions, SOC Injury, poisoning and procedural complications, SOC Infections and infestations). See examples in the table below.

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Example

PTs with Primary SOC General disorders and administration site conditions and Secondary SOC Cardiac disorders

PT Chest discomfort

PT Chest pain

PT Oedema peripheral

PT Sudden death

PT Localised oedema

PT Oedema due to cardiac disease

PT Peripheral oedema neonatal

PT Cardiac death 3.2.1 Overview by primary System Organ Class

This overview is recommended as a first step in data retrieval and for planning of further analysis. Display of all data ensures that all events will be seen and may be useful to identify data clusters by SOC. If the hierarchy is also displayed, clusters may occur at the HLGT or HLT levels. For a small dataset, this display by primary SOC may be all that is necessary.

Objectives:

Include all events (none are omitted)

Display all data in the entire MedDRA hierarchy

Method:

The primary SOC view including HLGTs, HLTs and PTs can be used for standard tables (clinical trials and postmarketing data) and for cumulative summaries (postmarketing data). Line listings (both clinical and postmarketing data) can also be displayed by primary SOC and PT. Depending on the reason for the output, it might be beneficial to use the primary SOC and PT display; for large datasets, display by SOC and by grouping terms (HLGTs and HLTs) may be preferable. Figure 4 is an example of such an output. The Internationally Agreed Order of SOCs was developed for consistency irrespective of language or alphabet (see Figure 5). The SOC order was based upon the relative importance of each SOC in AR/AE reports. Use of the Internationally Agreed Order may be applicable to certain regulatory functions, e.g., the SPC guideline and PSURs (see the MedDRA Introductory Guide and

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MedDRA ASCII files). Organizations that share data should agree on the order of SOCs when preparing data for presentation. Data displays in tables or in graphical presentations may facilitate understanding by the viewer. Figures 6, 7 and 8 are examples of such displays. Figures 9a and 9b display data for one compound in two patient populations. Within each patient population, the reports are split by SOC and by reporter. The upper bar of each pair represents numbers of reports from consumers (blue), and the lower bar represents reports from health care professionals (red). If further detail is needed, adverse events can be displayed by PT with decreasing frequency. In depth analysis requires medical expertise to define terms that should be aggregated.

Benefits:

Provides an overview of data distribution; helps identify areas of special interest that may need in depth analysis

Grouping terms aggregate related PTs, facilitating identification of medical conditions of interest

A PT will be displayed only once, preventing over-counting of terms

A primary SOC overview may be the only form of data display necessary for a small dataset

Limitations:

Because it is based on a PT-to-primary SOC assignment, there may be incomplete groupings of terms for a medical condition or syndrome as such terms may be distributed among different SOCs

Events may not be found where the user expects them due to MedDRA placement rules

Potential for a lengthy data output when applied to large datasets

3.2.2 Overall presentations of small datasets

When the safety profile consists of a small list of PTs (e.g., early in clinical development), a display of these PTs may be adequate. Figure 10 is an example of this.

18

3.2.3 Focused searches

Focused searches may be useful for further investigation of medical concepts of interest. For example, a focused search may be used to determine the number of cases or events of interest in response to a regulatory query. In certain situations, such as those listed below (note that this list is not all-inclusive), users may wish to design a specific search in addition to the Overview by Primary System Organ Class. (See Section 3.2.1).

Further examination of clusters seen in Primary SOC output

Previously identified safety concerns (e.g., known class effects, results from toxicology and animal studies, etc.)

Monitoring events of special interest

Responding to regulatory queries

Below are listed options for focused search approaches. The order of applying these approaches may depend on resources, expertise, systems or other factors.

3.2.3.1 Focused searches by secondary SOC assignments This focused search augments the Overview by Primary System Organ Class (see Section 3.2.1) by addressing secondary SOC assignments, thus providing a more comprehensive view of the data and taking advantage of MedDRA’s multi-axiality.

Method:

The method used for a focused search by secondary SOC assignment may depend on the database characteristics of the organization. Options include:

Query of the SOC, HLGT and HLT levels to include both the primary and secondary SOC assignments in the display

Output PTs in their secondary SOC locations programmatically (See Figure 11)

If the database does not allow automated output by secondary SOC, then perform the query using available processes (e.g., programming a list of all individual PTs in the primary and secondary SOC locations)

19

Example

Programming a List of PTs in Primary and Secondary SOC Locations

SOC Eye disorders

HLGT Vision disorders

HLT Visual field disorders

PT Hemianopia

PT Hemianopia heteronymous

PT Hemianopia homonymous

PT Scotoma (primary SOC location)

PT Tunnel vision

PT Uhthoff's phenomenon

PT Visual field defect

6 of 7 PTs are primary to SOC Nervous system disorders

Benefits:

Multi-axial links enhance the utility of the grouping terms. This method overcomes the primary SOC limitations as described under Section 3.2.1.

Limitations:

Still displays only terms that are represented in one SOC or HLGT/HLT which may not include all terms related to a medical condition

This method of display of PTs by both primary and secondary SOC assignments could lead to double counting of cases/events

Section 4 – STANDARDISED MedDRA QUERIES 4.1 – Introduction Standardised MedDRA Queries (SMQs) were created to standardize identification and retrieval of safety data. SMQs are a joint effort of the Council for International Organizations of Medical Sciences (CIOMS) and ICH (including MSSO and JMO) representing both industry and regulatory authorities. An SMQ is a grouping of terms from one or more SOCs that relate to a defined medical condition or area of interest. The terms included relate to signs, symptoms, diagnoses, syndromes, physical

20

findings, laboratory and other physiologic test data, etc. that are associated with the medical condition or area of interest. Users should carefully read the Introductory Guide for Standardised MedDRA Queries (SMQs) before applying an SMQ to fully understand the scope of the SMQ and to properly apply search options such as algorithms and weightings. 4.2 – SMQ Benefits As with all MedDRA-based queries, users of SMQs should be aware of several factors that may influence data retrieval including database characteristics, data conversion processes, coding conventions, and MedDRA versioning. For more details, see Section 3.1.

SMQ benefits include:

Application across multiple therapeutic areas

Validated reusable search logic

Standardized communication of safety information

Consistent data retrieval

Maintenance by MSSO and JMO

4.3 – SMQ Limitations

SMQs do not cover all medical topics or safety issues

SMQs evolve and undergo further refinement even though they have been tested during development

4.4 – SMQ Modifications and Organization-Constructed Queries If any modifications are made to term content or structure of an SMQ, it can no longer be called an “SMQ” but it should instead be referred to as a “modified MedDRA query based on an SMQ”. See Section 5.1 for further details on SMQ modification. Under no circumstances should a query constructed for the specific need of an organization be called an “SMQ” by its originator. This is to ensure that there is no confusion with the ICH-endorsed SMQs applied by other MedDRA users. Any alternate name for the organization-constructed query is acceptable as long as it could not be potentially confused with an ICH-endorsed SMQ. 4.5 – SMQs and MedDRA Version Changes Each SMQ relates to a specific MedDRA version. SMQs are part of each new MedDRA release, are maintained by MSSO and JMO, and correspond to the

21

terms present in that version of MedDRA. The SMQ version should always correspond to the MedDRA version of the data being searched. As with all searches of MedDRA-based data, it is important to document the MedDRA and SMQ versions used. Changes to SMQs that can occur with each MedDRA version include (but are not limited to) the following:

Addition of PTs

Inactivation of a PT (i.e., effectively “removing” a PT from an SMQ)

Change of term scope (e.g., a narrow term becomes a broad term)

Restructuring of an SMQ (e.g., change in the hierarchical position of an SMQ)

Creation of a new SMQ

For a full description of the types of changes that can occur to SMQs, please refer to the MedDRA “Change Request Information” document. (See Appendix, Section 6.1). Changes introduced with each new version are documented in the “What’s New” document for each MedDRA version. (The cumulative changes are contained within the ASCII files in the fields called “Term_addition_version” and “Term_last_modified_version”). The MedDRA version of the SMQ and the coded data being searched should be the same because mismatches could produce unexpected results. For example, if an SMQ from an older version of MedDRA is applied to data coded in a more recent version, data coded to terms that are not present in the older SMQ would not be retrieved.

Example

Consequence of Version Mismatch of Coded Data and SMQ

PT Dystonic tremor was added to SMQ Dystonia in MedDRA Version 16.0.

Using Version 15.1 of this SMQ – which does not contain this PT – would fail

to identify cases coded to this term in a database using

MedDRA Version 16.0. 4.6 – SMQs – Impact of MedDRA Legacy Data Conversion The conversion method for data originally coded in another terminology (e.g., COSTART) also impacts the application and output of SMQs. See Section 2.1.2, Impact of data conversion method.

22

4.7 – SMQ Change Requests Users are encouraged to submit Change Requests to MSSO and JMO to improve the utility of SMQs. A justification (and possibly testing data) for a submitted Change Request must be provided. The MSSO may require more time to evaluate SMQ Change requests than regular MedDRA Change Requests. Before submitting an SMQ Change Request, users should review the SMQ documentation for inclusion and exclusion criteria of the SMQ. 4.8 – SMQ Technical Tools The MSSO browsers (both the desktop and Web-based browsers) allow for searching and viewing the contents of SMQs and they include additional details such as the SMQ description (definition) and development notes. An Excel spreadsheet containing the terms in each production SMQ is available from MSSO and JMO. (See Appendix, Section 6.1). This spreadsheet allows a user to transfer SMQ terms to query tools. File specifications related to SMQs are found in “MedDRA ASCII and Consecutive Files Documentation” supplied with each MedDRA version. The MSSO Web site has a list of some system tools that provide technical support for SMQs. (See Appendix, Section 6.1). 4.9 – SMQ Applications SMQs were developed to address the high granularity and unique features of MedDRA and to maximize the likelihood that all terms related to a specific medical condition of interest are identified. The user should first review the list of available SMQs to determine which of them may be applicable to the question being asked. If an SMQ seems applicable, the user should check the documentation in the SMQ Introductory Guide to understand the purpose and definition of the SMQ. The user may also wish to review the term contents of the SMQ. Following application of the selected SMQ on coded data, search results (i.e., retrieved data) should then be evaluated against the question originally posed. The search output alone may not be sufficient for data assessment (e.g., frequency of a condition). Define and document criteria for case evaluation. Generally, more cases/events will be retrieved than will eventually be subjected to analysis due to “noise”. This is a more significant consideration for “broad” searches but in principle also applies to “narrow” searches. (See Section 4.10.1).

23

4.9.1 Clinical trials SMQs may be applied in the clinical trial setting – especially for aggregate data – where the safety profile has yet to be fully established. In this instance, most (if not all) available SMQs may be used, possibly on a routine basis. Alternatively, a user can apply an SMQ (or SMQs) that relates to a previously identified area of interest (e.g., from pre-clinical data or class effect) for further evaluation.

Example

Targeted Safety Study

When developing a data analysis plan for a targeted safety study, consider

using the narrow terms of an SMQ to aggregate events of interest.

4.9.2 Postmarketing

4.9.2.1 Focused searches A specific SMQ or a selection of SMQs may be used to retrieve relevant cases for subsequent medical review.

Example

Emerging Safety Signal

A company suspects an emerging signal of pancreatitis for a new HIV

product. SMQ Acute pancreatitis can be applied to the data.

4.9.2.2 Signal detection The entire set of SMQs may be used on the database for signal detection. The user may wish to use the narrow terms or more specific levels of hierarchical SMQs (i.e., a sub-search SMQ) to minimize dilution of the signal.

4.9.2.3 Single case alert

SMQs may be used to create a “watch list” (e.g., an automated notification system) to alert the user of incoming cases needing urgent review.

Example

Single Case Alert

A medical issue of interest needs to be communicated to a regulatory

24

Single Case Alert

authority as part of an agreed risk management plan. The SMQ narrow

search or more specific levels of a hierarchical SMQ may be applied to

identify potential cases of interest.

4.9.2.4 Periodic reporting

SMQs may help aggregate relevant cases for ongoing review of specific safety issues in periodic safety reports. SMQs may also be used for other routine reviews of aggregate data (e.g., reports of lack of efficacy) in the context of a periodic report. 4.10 – SMQ Search Options Some SMQs have options that may be used to refine a particular search. The most common option is use of narrow and broad search terms. By definition, a broad search includes both narrow and broad terms. Some SMQs are hierarchical (i.e., contain one or more sub-searches). Other SMQs use algorithms, and in one case (SMQ Systemic lupus erythematosus), weightings are assigned to particular terms for signs, symptoms and laboratory results to help identify cases.

4.10.1 Narrow and broad searches

Most SMQs have narrow and broad PTs. The narrow PTs have a greater likelihood of identifying only events of interest (high specificity) while the broad terms are intended to identify additional possible events (high sensitivity). Some events retrieved by the broad search terms may, upon further review, not relate to the condition of interest. The user can select the scope of the search (narrow or broad) that is most applicable to the question being asked. Figure 12 is an example of output of narrow and broad searches. When a compound is in early phase development or has only recently been marketed, it may be advisable to use the broad search.

Example

Use of Broad Search

If evaluating an emerging signal of lactic acidosis using SMQ Lactic acidosis,

narrow terms may be applied to identify events where the specific diagnosis

has been reported; however, events of reported signs and symptoms would

not be retrieved. If there is additional need to find cases where no specific

diagnosis (but mainly signs and symptoms) have been reported, then a broad

25

Use of Broad Search

search (i.e., narrow + broad search terms) should be applied.

4.10.2 Hierarchical SMQs

Several SMQs have a hierarchical structure (one or more levels of sub-searches of increasing specificity). The user can select the search that is most applicable to the question being asked or a combination of sub-search SMQs as needed. The SMQ Introductory Guide has explanatory notes on the appropriate use of each hierarchical SMQ. An example of a hierarchical SMQ is illustrated below (SMQ Haematopoietic cytopenias).

Haematopoietic cytopenias

(SMQ)

(20000027)

Haematopoietic cytopenias

affecting more than one type

of blood cell (SMQ)

(20000028)

Haematopoietic

erythropenia (SMQ)

(20000029)

Haematopoietic

leukopenia (SMQ)

(20000030)

Haematopoietic

thrombocytopenia

(SMQ)

(20000031)

Example

Use of SMQ Hierarchy

The medical condition of interest is thrombocytopenia. SMQ

Haematopoietic cytopenias may be too inclusive because sub-searches for

decreases of other hematopoietic cell lines (e.g., SMQ Haematopoietic leukopenia) are included. A user may wish to select only the sub-search

SMQ Haematopoietic thrombocytopenia in this instance.

4.10.3 Algorithmic SMQs

An algorithm provides for a combination of terms which – if retrieved in a single case – are more likely to identify a case of interest than isolated broad search terms (see table below). The broad terms of algorithmic SMQs are subdivided into categories that could be groupings of organ-specific signs or symptoms, laboratory terms, etc. (Note: the broad search categories are labeled B, C, D,

26

etc.). Using an algorithm may reduce the amount of “noise” (i.e., non-relevant cases). Using an algorithmic SMQ without applying the algorithm (i.e., simply applying the narrow and broad searches) will yield different results from those obtained using the algorithm.

Example

Algorithmic SMQ (SMQ Anaphylactic reaction)*

Category B – Upper

airway/Respiratory

Category C –

Angioedema/Urticaria,

etc.

Category D –

Cardiovascular/Hypotension

Acute respiratory

failure Allergic oedema Blood pressure decreased

Asthma Angioedema Blood pressure diastolic

decreased

Bronchial oedema Erythema Blood pressure systolic

decreased

Algorithm:

Case = A (Narrow terms – not included in the table)

Or term from Category B and term from Category C

Or term from either Category B or Category C plus term from

Category D

* Not all terms in these categories are listed in the table SMQ Systemic lupus erythematosus is an algorithmic SMQ with assigned weights for its included PTs (e.g., PT Pleural effusion = 3); a total weighted score greater than 6 suggests a case of interest. Users should not assume that all software tools support algorithmic SMQs. 4.11 – SMQ and MedDRA Grouping Terms Data retrieved using MedDRA grouping terms (HLGTs, HLTs) may differ from those retrieved using a related SMQ.

27

Example

Comparison – SMQ and Grouping Terms

Cardiac arrhythmia is a suspected issue (e.g., by review of a primary SOC

output of all data). If events retrieved by using HLGT Cardiac arrhythmias

are compared to those retrieved by SMQ Cardiac arrhythmias, more events

may be retrieved by the SMQ because it includes additional terms from

other SOCs such as SOC Investigations. Section 5 – CUSTOMIZED SEARCHES MedDRA allows for a variety of searching options as described above. However, there will be situations when a customized search is needed. 5.1 – Modified MedDRA Query Based on an SMQ Do not modify the term content or structure of an SMQ unless there is a compelling reason to do so since altering it in any way makes it non-standard. (See Section 4.4). If an SMQ is modified in any way, it should be referred to as a “modified MedDRA query based on an SMQ”. All modifications to the original SMQ should be documented. If a modified MedDRA query based on an SMQ is to be used on an ongoing basis, version updates and maintenance of the query are the responsibility of the organization that created it.

Example

Modified MedDRA Queries based on SMQs

Additional PTs are

needed

A product is being investigated for a possible safety

signal of dementia, and the user wishes to use SMQ

Dementia. For this particular product, PT Disturbance in attention may be needed.

Exclusion of PTs An antipsychotic product is being investigated for

28

Modified MedDRA Queries based on SMQs

potential QT prolongation and also has a well-

described association with hypotension and fainting.

When using SMQ Torsade de pointes/QT prolongation

(broad search), the user may wish to exclude PT

Syncope to prevent excess “noise” in data retrieval.

Changing the scope

(narrow or broad)

of an SMQ term

A product is being investigated for severe cutaneous

adverse reactions (SCARs) including a potential for

drug rash with eosinophilia and systemic symptoms

(also called DRESS syndrome). SMQ Severe cutaneous adverse reactions has PT Drug reaction with eosinophilia and systemic symptoms as a broad search

term. For this query, it may be useful to include PT

Drug reaction with eosinophilia and systemic symptoms

in the narrow search. 5.2 – Customized Queries Consider these points when constructing a customized query for MedDRA-coded data:

Those responsible for constructing a customized query should:

o Have medical knowledge

o Know the structure and characteristics of MedDRA (e.g., hierarchy, multi-axiality) and the general content of MedDRA groupings (SOCs, HLGTs, and HLTs)

o Understand the characteristics and structure of the data

The specificity of the search should be defined.

Initial focus should be on SOCs related to the condition of interest. For example, a customized search for a renal condition should start with SOC Renal and urinary disorders.

The non multi-axial SOCs (SOC Investigations, SOC Surgical and medical procedures and SOC Social circumstances) should always be reviewed. Also, it may be useful to review terms in other SOCs that are not organ systems (e.g., SOC General disorders and administration site conditions, SOC Injury, poisoning and procedural complications and SOC Pregnancy, puerperium and perinatal conditions).

29

It may be useful to identify relevant query terms by the following approaches:

o A “bottom-up” survey of MedDRA (terms at the LLT and PT levels initially)

o A “top-down” survey of MedDRA (starting at the SOC level and drilling down through the hierarchy)

Consider looking at secondary links for multi-axial terms since additional relevant query terms could be found. For example, PT Dyspnoea can be found with other respiratory symptoms PTs in its primary SOC Respiratory, thoracic and mediastinal disorders, and it can also be found with related cardiac symptoms in its secondary SOC Cardiac disorders.

Include grouping terms (HLGTs, HLTs) when possible (remembering the caveats described in Section 2.5.1).

In general, queries should be built on PTs and grouping terms. Unless very specific concepts (e.g., bacterial species) are needed, avoid using LLTs to build queries.

Consider saving the customized query for future use; maintenance is necessary for MedDRA version changes.

A customized query that may be useful to other MedDRA users can be submitted to the MSSO as a Change request for possible development as an SMQ.

Section 6 – APPENDIX 6.1 – Links and References

Document Link

MedDRA Term

Selection: Points

to Consider

document (also

available on JMO

and ICH Web

sites)

http://meddramsso.com/subscriber_library_ptc.asp

MedDRA

Introductory

Guide

http://meddramsso.com/files_acrobat/intguide_16_0_En

glish_update.pdf

30

Document Link

Introductory

Guide for

Standardised

MedDRA Queries

(SMQs)

http://meddramsso.com/files_acrobat/SMQ_intguide_16

_0_English_update.pdf

Pediatric and

Gender Adverse

Event Term Lists

https://meddramsso.com/subscriber_download_tools_ped

iatric.asp

ICH E2E:

Pharmacovigilance

Planning

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Pro

ducts/Guidelines/Efficacy/E2E/Step4/E2E_Guideline.pdf

MedDRA Change

Request

Information

document

http://meddramsso.com/subscriber_download_change_re

quest.asp

MedDRA Web-

based Browser

https://meddramsso.com/subscriber_download_tools_wb

b.asp

MedDRA Desktop

Browser

https://meddramsso.com/subscriber_download_tools_bro

wser.asp

MedDRA Version

Report (lists all

changes in new

version) *

https://meddramsso.com/secure/subscriber_download_tr

anslations.asp

MedDRA Version

Analysis Tool

(compares any

two versions) *

http://www.meddramsso.com/subscriber_download_tools

_mvat.asp

Production SMQ

spreadsheet* http://meddramsso.com/subscriber_smq.asp

List of system

tools that support

SMQs

http://meddramsso.com/subscriber_download_tools_thir

dparty.asp

* Requires user ID and password to access

31

6.2 – Membership of the ICH Points to Consider Working Group 6.2.1 Current members of the ICH Points to Consider Working Group

Affiliation Member

Commission of the European

Communities

Sarah Vaughan

Maria Luisa Casini

European Federation of

Pharmaceutical Industries

Associations

Hilary Vass*

Christina Winter†

Health Canada Alison Bennett

Lynn Macdonald

Japanese Maintenance Organization

Osamu Handa

Kazuyuki Sekiguchi

Reiji Tezuka

Japan Pharmaceutical Manufacturers

Association Yo Tanaka

MedDRA MSSO Judy Harrison

Patricia Mozzicato

Ministry of Health, Labour and

Welfare

Shinichi Okamura

Makiko Isozaki

Hideyuki Kondou

Shinichi Watanabe

Pharmaceutical Research and

Manufacturers of America

Anna-Lisa Kleckner

JoAnn Medbery

US Food and Drug Administration

John (Jake) Kelsey*

Sonja Brajovic * Current co-Rapporteurs † Former Rapporteur 6.2.2 Former members of the ICH Points to Consider Working Group

Affiliation Member

Commission of the European Dolores Montero

32

Affiliation Member

Communities Carmen Kreft-Jais

Morell David

European Federation of

Pharmaceutical Industries

Associations

Barry Hammond†; Reinhard

Fescharek†

Health Canada Heather Morrison; Michelle Séguin;

Heather Sutcliffe; Bill Wilson

Japanese Maintenance Organization Akemi Ishikawa; Yasuo Sakurai; Yuki

Tada

Japan Pharmaceutical Manufacturers

Association

Takayoshi Ichikawa; Akemi Ishikawa;

Satoru Mori; Yasuo Sakurai;

Kunikazu Yokoi

MedDRA MSSO JoAnn Medbery

Ministry of Health, Labour and

Welfare

Tamaki Fushimi; Wakako Horiki;

Kazuhiro Kemmotsu; Tatsuo Kishi;

Chie Kojima; Emiko Kondo; Kemji

Kuramochi; Tetsuya Kusakabe; Kaori

Nomura; Izumi Oba; Yoshihiko Sano;

Nogusa Takahara; Kenichi Tamiya;

Daisuke Tanaka; Takashi Yasukawa;

Go Yamamoto; Manabu Yamamoto;

Nobuhiro Yamamoto

Pharmaceutical Research and

Manufacturers of America

David Goldsmith; Sidney Kahn; Susan

M. Lorenski; Margaret M. Westland†

US Food and Drug Administration Miles Braun; Andrea Feight; Brad

Leissa; Toni Piazza-Hepp † Former Rapporteur 6.3 – Figures

33

OTHER TERMINOLOGY

PREFERRED TERMS

NO. OF

EVENTS

MEDDRA VERSION 16.0

PREFERRED TERMS

NO. OF

EVENTS

Infection 15 Upper respiratory tract

infection

Nasopharyngitis

Infection

Lower respiratory tract

infection

Skin infection

7

2

1

4

1

Abdominal pain 9 Abdominal pain

Abdominal pain upper

Abdominal tenderness

4

3

2

Accidental injury 4 Injury

Skin laceration

Ligament sprain

Back injury

1

1

1

1 Figure 1 – How data coded to a single concept from another terminology may be expressed by several PTs in MedDRA

OTHER TERMINOLOGY MedDRA Version 16.0

Reported

Event

(% subjects)

Coded Term

(% subjects)

Body

System/SOC

(% subjects)

PT

(% subjects)

SOC

(% subjects)

Hyperglycaemia

(4.1)

Hyperglycemia

(10.5)

Metabolism

& nutritional

disorders

(10.5)

Hyperglycaemia

(4.1)

Metabolism

and nutrition

disorders

(4.1)

Increased

blood sugar

(2.7)

Glucose

increased (2.2)

Blood glucose

high (1.0)

Blood glucose

increased (6.4)

Investigations

(6.4)

Increasing

glucoses (0.5) Figure 2 – Multiple MedDRA terms may be used to code similar medical conditions included in a “disorder SOC”; associated laboratory findings are in SOC Investigations

34

Preferred Terms Events/Cases Comment

Version 15.1 Version 16.0

AIDS

encephalopathy

15 0

(no longer a PT)

In MedDRA Version 15.1, AIDS encephalopathy was a PT

and in Version 16.0 it was

demoted to an LLT under PT

AIDS dementia complex. AIDS dementia

complex

5 20

Figure 3 – Impact of MedDRA version changes – demotion of a PT

35

Figure 4 – Primary SOC output listing – example. Note that some PTs are multi-axial, however, this figure shows only the primary SOC assignments

MedDRA Version 16.0

English Alphabetical Order

MedDRA Version 16.0

Internationally Agreed Order

Blood and lymphatic system disorders Infections and infestations

Cardiac disorders Neoplasms benign, malignant and unspecified (incl cysts

and polyps)

Congenital, familial and genetic disorders Blood and lymphatic system disorders

Ear and labyrinth disorders Immune system disorders

Endocrine disorders Endocrine disorders

Eye disorders Metabolism and nutrition disorders

Gastrointestinal disorders Psychiatric disorders

General disorders and administration site conditions Nervous system disorders

Hepatobiliary disorders Eye disorders

Immune system disorders Ear and labyrinth disorders

36

MedDRA Version 16.0

English Alphabetical Order

MedDRA Version 16.0

Internationally Agreed Order

Infections and infestations Cardiac disorders

Injury, poisoning and procedural complications Vascular disorders

Investigations Respiratory, thoracic and mediastinal disorders

Metabolism and nutrition disorders Gastrointestinal disorders

Musculoskeletal and connective tissue disorders Hepatobiliary disorders

Neoplasms benign, malignant and unspecified (incl

cysts and polyps) Skin and subcutaneous tissue disorders

Nervous system disorders Musculoskeletal and connective tissue disorders

Pregnancy, puerperium and perinatal conditions Renal and urinary disorders

Psychiatric disorders Pregnancy, puerperium and perinatal conditions

Renal and urinary disorders Reproductive system and breast disorders

Reproductive system and breast disorders Congenital, familial and genetic disorders

Respiratory, thoracic and mediastinal disorders General disorders and administration site conditions

Skin and subcutaneous tissue disorders Investigations

Social circumstances Injury, poisoning and procedural complications

Surgical and medical procedures Surgical and medical procedures

Vascular disorders Social circumstances

Figure 5 – The alphabetical SOC order (in English) and the Internationally Agreed Order of SOCs

37

Figure 6 – Example of a graphical display (frequency by primary SOC)

38

Figure 7 – Example of a graphical display (frequency by primary and secondary SOC)

39

Figure 8 – Example of a tabular display (frequency by primary SOC)

Figure 9a – The upper bar of each pair represents numbers of reports from Consumers (blue) and the lower bar reports from Health Care Professionals (red) (Population 1)

0 500 1000 1500 2000 2500 3000

Congenital, familial and genetic disorders

Pregnancy, puerperium and perinatal conditions

Surgical and medical procedures

Social circumstances

Neoplasms benign, malignant and unspecif ied

Endocrine disorders

Hepatobiliary disorders

Infections and infestations

Metabolism and nutrition disorders

Blood and lymphatic system disorders

Renal and urinary disorders

Respiratory, thoracic and mediastinal disorders

Immune system disorders

Vascular disorders

Cardiac disorders

Eye disorders

Musculoskeletal and connective tissue disorders

Ear and labyrinth disorders

Reproductive system and breast disorders

Injury, poisoning and procedural complications

Investigations

Gastrointestinal disorders

General disorders and administration site conditions

Psychiatric disorders

Skin and subcutaneous tissue disorders

Nervous system disorders

Syste

m O

rgan

Cla

ss

Number of Reports

40

Figure9b – The upper bar of each pair represents numbers of reports from Consumers (blue) and the lower bar reports from Health Care Professionals (red) (Population 2)

0 2000 4000 6000 8000 10000 12000 14000 16000

Surgical and medical proceduresCongenital, familial and genetic disorders

Endocrine disordersNeoplasms benign, malignant and unspecified

Social circumstancesHepatobiliary disorders

Pregnancy, puerperium and perinatal conditionsBlood and lymphatic system disorders

Infections and infestationsRenal and urinary disorders

Metabolism and nutrition disordersInjury, poisoning and procedural complications

Reproductive system and breast disordersEar and labyrinth disorders

Vascular disordersInvestigationsEye disorders

Respiratory, thoracic and mediastinal disordersMusculoskeletal and connective tissue disorders

Cardiac disordersImmune system disorders

General disorders and administration siteGastrointestinal disorders

Psychiatric disordersNervous system disorders

Skin and subcutaneous tissue disorders

Sy

ste

m O

rga

n C

las

s

Number of Reports

41

Figure 10 – For a small dataset, a display of PTs may be adequate

SOC Infections and infestations

Primary SOC Analysis

Adverse Event (MedDRA v16.0) 25 mg

MyDrug

(N=44)

Placebo

(N=15)

SOC Infections and infestations 14 (31.8%) 4 (26.7%)

PT Upper respiratory tract infection 5 2

PT Sinusitis 3 0

PT Urinary tract infection 2 1

PT Ear infection 2 0

PT Viral infection 2 0

PT Bronchitis 1 0

PT Influenza 1 0

PT Localised infection 0 1

PT Lower respiratory tract infection 1 0

PT Pneumonia 1 0

42

Adverse Event (MedDRA v16.0) 25 mg

MyDrug

(N=44)

Placebo

(N=15)

PT Tooth abscess 1 0 Secondary SOC Analysis (same data as above)

Adverse Event (MedDRA v16.0) 25 mg

MyDrug

(N=44)

Placebo

(N=15)

SOC Respiratory, thoracic and mediastinal disorders

PT Upper respiratory tract infection 5 2

PT Sinusitis 3 0

PT Bronchitis 1 0

PT Influenza 1 0

PT Lower respiratory tract infection 1 0

PT Pneumonia 1 0

SOC Infections and infestations

PT Viral infection 2 0

PT Localised infection 0 1

SOC Renal and urinary disorders

PT Urinary tract infection 2 1

SOC Ear and labyrinth disorders

PT Ear infection 2 0

SOC Gastrointestinal disorders

PT Tooth abscess 1 0 Figure 11 – Programmed primary and secondary SOC outputs

Asthma/bronchospasm (SMQ) Cases – Narrow Search

(since 1-JAN-2008)

ID MedDRA_PT REPORT_VERBATIM DATE_CREATED

------------------------------------------------------------------------------------------------------------

045 Asthma Asthma attack 01-APR-2008

063 Asthma Severe asthma 10-JUN-2008

060 Asthma exercise induced Asthma when exercising 30-MAY-2008

091 Bronchospasm Spasms, bronchial 12-AUG-2008

074 Bronchospasm Bronchoconstriction 03-JUL-2008

43

100 Bronchial hyperreactivity Airways hyperreactive 20-SEP-2008

069 Bronchial hyperreactivity Reactive airways disease 21-JUN-2008

Asthma/bronchospasm (SMQ) Cases – Broad Search

(since 1-JAN-2008)

ID MedDRA_PT REPORT_VERBATIM DATE_CREATED

------------------------------------------------------------------------------------------------------------

023 Allergic respiratory disease Respiratory (allergy) disorder 18-FEB-2008

045 Asthma Asthma attack 01-APR-2008

063 Asthma Severe asthma 10-JUN-2008

060 Asthma exercise induced Asthma when exercising 30-MAY-2008

016 Bronchial obstruction Bronchial obstruct. 16-JAN-2008

039 Bronchial obstruction Bronchus obstruction 14-MAR-2008

091 Bronchospasm Spasms, bronchial 12-AUG-2008

074 Bronchospasm Bronchoconstriction 03-JUL-2008

100 Bronchial hyperreactivity Airways hyperreactive 20-SEP-2008

069 Bronchial hyperreactivity Reactive airways disease 21-JUN-2008

088 Obstructive airways disorder Obstructive airways disorder 29-JUL-2008

049 Obstructive airways disorder Obstructed airways dis. 20-APR-2008

022 Wheezing Wheeze 16-FEB-2008

031 Wheezing Wheezes 02-MAR-2008

106 Wheezing Wheezing 28-SEP-2008

046 Wheezing Wheezing (acute) 06-APR-2008 Figure 12 – Results of Narrow and Broad SMQ Searches